Prenatal Corticosteroid Impact on Hippocampus

产前皮质类固醇对海马的影响

基本信息

批准号：
6803019
负责人：
LIBOR VELISEK
金额：
$ 19.83万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-01 至 2005-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Corticosteroid therapy is widely used during the third trimester of pregnancy to prevent respiratory distress syndrome in prematurely born neonates. A single course of this therapy has no long-term harmful effects. However, multiple courses of corticosteroid therapy with long-lasting elevations of corticosteroids are frequently used. Animal data indicate that long-term prenatal corticosteroid increases during the last third of pregnancy may adversely affect brain development, especially hippocampus-associated functions such as learning and memory. The purpose of this proposal is to establish a rat model of prenatal or early postnatal multiple-course corticosteroid administration to determine the effects of repeated corticosteroid therapy on hippocampal function (tested postnatally in hippocampal- related seizure susceptibility, behavioral and learning tests in vivo) and morphology (assessed using neuronal proliferation, stereological neuronal counts, and rate of neuronal death). The proposal will further investigate the possibility that there may be a synergy between the effects of such doses of corticosteroids that do not produce harmful effects and the effects of another subthreshold postnatal impact (a febrile seizure). The synergy of these two factors will then result in adverse effects on hippocampal function and structure ("two-hit" hypothesis). Finally, the experiments will determine whether the harmful effects of repeated corticosteroid treatment may be ameliorated by the exposure of the affected offspring to an enriched environment. Methods include prenatal administration of corticosteroids, kainic acid-induced seizures, hippocampal kindling, open field, horizontal bar and elevated plus maze tests, labeling of newly born neurons with BrdU, fluorescent staining for apoptotic/necrotic neurons, stereological neuronal counts in the hippocampus using light and confocal microscopy, and the exposure of the rats to an enriched environment. The data of this proposal will be critical for determining long-term adverse effects of multiple course prenatal corticosteroid therapy and for the ameliorating these effects in the offspring.

描述（由申请人提供）：皮质类固醇治疗广泛用于妊娠晚期，以预防早产新生儿出现呼吸窘迫综合征。该疗法的单疗程不会产生长期有害影响。然而，经常使用皮质类固醇激素长期升高的多个疗程。动物数据表明，在怀孕的最后三分之一期间长期增加产前皮质类固醇可能会对大脑发育产生不利影响，尤其是与海马体相关的功能，例如学习和记忆。本提案的目的是建立产前或产后早期多疗程皮质类固醇给药的大鼠模型，以确定重复皮质类固醇治疗对海马功能的影响（产后在海马相关的癫痫易感性、行为和学习测试中进行体内测试）和形态学（使用神经元增殖、体视神经元计数和神经元死亡率进行评估）。该提案将进一步调查这种不会产生有害影响的剂量皮质类固醇的作用与另一种阈下产后影响（热性惊厥）的作用之间可能存在协同作用的可能性。这两个因素的协同作用将对海马功能和结构产生不利影响（“两次打击”假说）。最后，实验将确定是否可以通过将受影响的后代暴露在丰富的环境中来减轻重复皮质类固醇治疗的有害影响。方法包括产前给予皮质类固醇、红藻氨酸诱导的癫痫发作、海马点燃、旷场、水平条和高架十字迷宫测试、用 BrdU 标记新生神经元、凋亡/坏死神经元的荧光染色、使用立体学方法对海马中的神经元进行计数。光学和共焦显微镜，以及将大鼠暴露于丰富的环境中。该提案的数据对于确定多疗程产前皮质类固醇治疗的长期不良影响以及改善后代的这些影响至关重要。